Qingdao University, Qingdao, 266071, China; Eye Hospital of Shandong First Medical University (Shandong Eye Hospital), Jinan, 250000, Shandong, China; State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Qingdao, 266071, China; School of Ophthalmology, Shandong First Medical University, Jinan, 250000, Shandong, China.
State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Qingdao, 266071, China; School of Ophthalmology, Shandong First Medical University, Jinan, 250000, Shandong, China.
Exp Eye Res. 2023 Jun;231:109464. doi: 10.1016/j.exer.2023.109464. Epub 2023 Apr 2.
Corneal endothelium is mostly sensitive to oxidative pressure and mitochondrial dysfunction. However, the oxidative-antioxidant mechanism of corneal endothelial cells (CECs) remains partially defined. Silent information regulator 1 (SIRT1) is a well-studied therapeutic target of oxidative damage. This study aimed to determine the SIRT1 expression in ultraviolet A (UVA)-induced corneal endothelial damage and explore potential drugs to repair corneal endothelial oxidative injury. In this study, we showed that CECs exhibited cellular apoptosis, reactive oxygen species (ROS) accumulation and decreased SIRT1 expression. In addition, UVA induced the imbalance of mitochondrial homeostasis and function, involving in mitochondrial membrane potential, mitochondrial fusion/fission and mitochondrial energy metabolism. SRT1720, the SIRT1 activator, effectively increased SIRT1 expression and attenuated UVA-induced oxidative damage in CECs. The therapeutic effects of SRT1720 for corneal endothelial oxidative damage were also verified in UVA-irradiated mice model. Our findings indicated that SIRT1 maintained the oxidant-antioxidant balance in corneal endothelium, suggesting a new promising therapeutic target for corneal endothelial dysfunction.
角膜内皮对氧化压力和线粒体功能障碍非常敏感。然而，角膜内皮细胞（CEC）的氧化-抗氧化机制仍部分定义。沉默信息调节因子 1（SIRT1）是氧化损伤的一个研究得很好的治疗靶点。本研究旨在确定紫外线 A（UVA）诱导的角膜内皮损伤中的 SIRT1 表达，并探索潜在的药物来修复角膜内皮氧化损伤。在这项研究中，我们表明 CEC 表现出细胞凋亡、活性氧（ROS）积累和 SIRT1 表达减少。此外，UVA 诱导了线粒体动态平衡和功能的失衡，涉及线粒体膜电位、线粒体融合/裂变和线粒体能量代谢。SIRT1 激活剂 SRT1720 可有效增加 SIRT1 表达，并减轻 CEC 中 UVA 诱导的氧化损伤。SRT1720 对角膜内皮氧化损伤的治疗效果也在 UVA 照射的小鼠模型中得到了验证。我们的研究结果表明，SIRT1 维持了角膜内皮的氧化还原平衡，为角膜内皮功能障碍提供了一个新的有希望的治疗靶点。
